Abstract
Aims. Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and macrophages play a key role in this process. The aim of this study was to discover the role of IκB kinase α (IKKα) in macrophages in the process of AKI-to-CKD transition. Main Methods. We crossed lyz2-Cre mice with IKKα-floxed mice to generate mice with IKKα ablation in macrophages (Mac IKKα-/-). A mouse renal ischemia/reperfusion injury (IRI) model was induced by clamping the renal artery for 45 minutes. Treated mice were evaluated for blood biochemistry, tissue histopathology, and fibrosis markers. Macrophages were isolated from the peritoneal cavity for coculturing with tubular epithelial cells (TECs) and flow cytometry analysis. Key Findings. We found that fibrosis and kidney function loss after IRI were significantly alleviated in Mac IKKα-/- mice compared with wild-type (WT) mice. The expression of fibrosis markers and the infiltration of M2 macrophages were decreased in the kidneys of Mac IKKα-/- mice after IRI. The in vitro experiment showed that the IRI TECs cocultured with IKKα-/- macrophages (KO MΦs) downregulated the fibrosis markers accompanied by a downregulation of Wnt/β-catenin signaling. Significance. These data support the hypothesis that IKKα is involved in mediating macrophage polarization and increasing the expression of fibrosis-promoting inflammatory factors in macrophages. Therefore, knockdown of IKKα in macrophages may be a potential method that can be used to alleviate the AKI-to-CKD transition after IRI.
Highlights
Chronic kidney disease (CKD) usually leads to end-stage renal disease (ESRD), which is a severe health problem worldwide [1, 2]
The mechanism underlying the acute kidney injury (AKI)-to-CKD transition has been studied in-depth in recent years, and the immune response to the infiltration of inflammatory cells was thought to play a key role in the process leading to the AKI-to-CKD transition [6]
Our study demonstrated that ablation of macrophage IKKα ameliorates kidney fibrosis, accompanied by less M2 macrophage infiltration in the kidneys after ischemia/reperfusion injury (IRI) inflammation, and inhibits the profibrotic pathway in renal tubular epithelial cells (TECs)
Summary
Chronic kidney disease (CKD) usually leads to end-stage renal disease (ESRD), which is a severe health problem worldwide [1, 2]. Because renal tubular epithelial cells (TECs) have the potential for self-repair, it was thought that the function and structure can recover completely after acute kidney injury (AKI). Patients with AKI who develop CKD are common, and recent epidemiological studies have demonstrated that AKI contributes to the development of CKD [4]. The mechanism underlying the AKI-to-CKD transition has been studied in-depth in recent years, and the immune response to the infiltration of inflammatory cells was thought to play a key role in the process leading to the AKI-to-CKD transition [6]. Studies showed that M2 macrophages accumulate in the injured kidney, leading to secretion of profibrotic growth factors, and promote the production of extracellular matrix [9, 12, 13]
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